(Revised Abstract) DESCRIPTION (provided by applicant): Carcinomas, including those of the prostate, breast, and ovary account for over 80,000 annual fatalities in the United States. While treatable in their earliest forms, these cancers are difficult to detect early and are often lethal once metastasis has occurred. Thus, routine screening and early detection are critical practices. Existing screening and diagnostic methods do not detect a large proportion (over 30%) of these cancers. Thus, new means for diagnosis and therapy are essential in meeting this health care challenge. We propose that molecules able to specifically target surface antigens of prostate, breast, and ovarian carcinomas will lead to improved detection and treatment modalities. Molecules that target cancer cells have been identified previously; however, agents selected in vitro often behave poorly in vivo. We hypothesize that development of cancer imaging agents with optimal binding properties (i.e. affinity, specificity) as well as in vivo stability and targeting propensity will be effectively realized through a combination of synthetic and novel in vivo combinatorial chemical approaches. To this end, we previously exploited combinatorial bacteriophage (phage) display technologies to isolate an assortment of peptides that bind tumor-associated antigens. Targeted antigens include the Thomsen-Friedenreich (TF) glycoantigen and the ErbB-2 receptor - both overexpressed on the surface of prostate, breast, and ovarian adenocarcinomas, and prostate specific membrane antigen (PSMA), overexpressed on prostate carcinomas. The Specific Aims of this application involve convergent approaches to improve the efficacy of peptides that target the tumor-associated antigens TF, ErbB-2 and PSMA for in vivo diagnostic imaging applications. First, tumor-targeting ability of the peptides will be improved through chemical coupling of multi-valent peptides with specificities for different receptors such as the TF antigen and PSMA. Secondly, superior peptide sequences for in vivo applications will be defined through affinity maturation of phage display libraries enriched in tumor-avid consensus sequences in vivo in tumor-bearing mice. Peptides with desirable stability and distribution properties will emerge due to the very nature of their selection from carcinomas in vivo. Lead peptides will be radiolabeled with 99mTc or 111In by incorporation of selected metal chelation moieties within the peptide structure. Alternatively, phage bearing the tumor-avid peptides will be labeled and explored as novel imaging agents. Pharmacokinetic evaluation of these peptides and phage in human tumor xenograft mouse models of prostate, breast, and/or ovarian cancer, coupled with diagnostic scintigraphic imaging, will identify the optimum tumor targeting radiolabeled peptide(s).